Impact of TRK-Fused Gene (TFG) pathogenic mutations on the regulation of autophagy and mitochondria homeostasis: molecular mechanisms and clinical opportunities.

The TRK-Fused Gene (TFG) codes for a ubiquitously expressed protein which, in physiological conditions, acts a COPII-vesicles regulator at the Endoplasmic Reticulum-Golgi Intermediate Compartment (ERGIC) interface. TFG is responsible for the distribution of COPII transport carriers, upon their scission from the ER, and mediates short-distance vesicle transport, via phase separation. We previously demonstrated TFG involvement in autophagy, through the interaction with autophagy regulators proteins, such as the upstream kinase ULK1 and the mATG8 family member LC3C. Autophagy is a highly regulated cellular mechanism, responsible for the dismissal of long-lived or damaged organelles as well as of bulk protein aggregates, and its dysfunction contributes to various neurodegenerative disorders. TFG mutations have been identified in three extremely rare disease such as, the autosomal dominant Hereditary Motor and Sensory Neuropathy with Proximal predominance (HMSN-P; prevalence unknown), a complex form of autosomal recessive Spastic Paraplegia (SPG57;<1/106), the Autosomal dominant Charcot-Marie-Tooth disease type 2 (CMT2;<1/106). Shedding lights on the role played by TFG in physiological vs. pathological conditions, as well as on how pathogenic mutations impact on cell homeostasis could be the key to the identification of new therapeutic target and/or pharmacological strategies (e.g., autophagy boosting). Here we investigated on how pathological TFG mutations impact autophagy activation/execution and mitochondrial quality control, thus resulting into protein aggregates accumulation and mitochondria dysfunction, a common feature of these diseases. Moreover, we verified whether pharmacological modulation of autophagy could ameliorate the pathogenic phenotypes.